Abstract
Ribosome degradation through the autophagy-lysosome pathway is crucial for cell survival during nutrient starvation, but whether it occurs under normal growth conditions and contributes to animal physiology remains unaddressed. In this study, we identified RNST-2, a C. elegans T2 family endoribonuclease, as the key enzyme that degrades ribosomal RNA in lysosomes. We found that loss of rnst-2 causes accumulation of rRNA and ribosomal proteins in enlarged lysosomes and both phenotypes are suppressed by blocking autophagy, which indicates that RNST-2 mediates autophagic degradation of ribosomal RNA in lysosomes. rnst-2(lf) mutants are defective in embryonic and larval development and are short-lived. Remarkably, simultaneous loss of RNST-2 and de novo synthesis of pyrimidine nucleotides leads to complete embryonic lethality, which is suppressed by supplements of uridine or cytidine. Our study reveals an essential role of autophagy-dependent degradation of ribosomal RNA in maintaining nucleotide homeostasis during animal development.
Highlights
Macroautophagy delivers cytoplasmic materials such as protein aggregates and organelles to lysosomes for degradation
We found that qx245 carried a G-to-A mutation in rnst-2 that resulted in the replacement of Gly 119 by Glu (Figure 1—figure supplement 2L). bp555, Figure 1. rnst-2 mutants accumulate enlarged lysosomes. (A–I) Confocal fluorescence images of embryos at the 4-fold stage (4F, A–C), larvae 1 (L1, D– F) and adult hypodermis (G–I) in wild-type (WT, A, D, G), rnst-2(qx245) (B, E, H) and rnst-2(bp555) (C, F, I) expressing LAAT-1::GFP. (J–L”) Confocal fluorescence images of the hypodermis in wild-type (J–J00), rnst-2 (K–K00) and rnst-2(bp555) (L–L00) adults expressing LAAT-1::GFP and stained by Lysotracker red
RNST-2 degrades ribosomal RNA delivered by autophagy in lysosomes
Summary
Macroautophagy (hereafter referred to as autophagy) delivers cytoplasmic materials such as protein aggregates and organelles to lysosomes for degradation. It is not surprising that autophagic degradation of ribosomes is crucial for survival of yeast cells in nutrient starvation (Kraft et al, 2008) It remains unclear whether mature ribosomes are degraded through autophagy under normal growth conditions and whether ribosome degradation contributes to animal physiology. Impairing autophagy or lysosome function leads to reduced hatching rate and retarded embryonic development (Zhao et al, 2009; Tian et al, 2009; Liu et al, 2012; Sun et al, 2011) It is unclear whether ribosomes, which contain abundant proteins and RNAs, may be used as a nutrient source for development. Our data indicate that autophagy-dependent degradation of ribosomal RNA is important for maintaining nucleotide homeostasis, which is essential for development
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